PROJECT SUMMARY This proposal describes a 3-year career development program and research strategy through which the Candidate will bolster her clinical epidemiology expertise with research capacity in genome science and bioinformatics and investigate the genetic underpinnings of parathyroid hormone concentrations. The principal investigator has completed a PhD at the University of Washington (UW) in Epidemiology, and post-doctoral training at the Kidney Research Institute, Division of Nephrology, Department of Medicine at the UW. She will expand upon her scientific skills through a focused career development plan and training in molecular genetics as applied to parathyroid hormone dysregulation in adults. Dr. Bruce Psaty is Professor of Medicine at UW and will mentor the principal investigator's scientific and career development. Dr. Psaty is a globally recognized leader in the genetic epidemiology of cardiovascular disease. An advisory committee of scientists, including Dr. Deborah Nickerson who has expertise in the applying robust methods for next- generation sequencing technology and Dr. Ronit Katz who is a well-established biostatistician, will provide additional career and project guidance. In addition, intensive workshops, coursework at UW and the Cold Spring Harbor Laboratory, a fellowship program at UT Health, seminars, journal clubs, and specific analytic technique training will accompany ample protected research time. The academic environment in the Department of Nephrology at UW supports the development of independent, translational investigators. Scientific investigations will focus on the genetic mechanisms of circulating parathyroid hormone (PTH), the Disorders of PTH have important clinical consequences. Primary hyperparathyroidism is classically associated with bone disease, kidney stones, and gastrointestinal dysmotility. Secondary hyperparathyroidism develops progressively in chronic kidney disease (CKD), contributing to the pathogenesis of CKD-mineral and bone disorder. In the general population, higher serum PTH concentrations are associated with hypertension, left ventricular hypertrophy, and fractures. essential regulatory hormone for calcium homeostasis. The underlying regulatory mechanism for of parathyroid hormone is unknown and there exists marked inter- individual variation in PTH independent of known factors. A recent genome-wide association study of PTH concentrations revealed a robust and strong association for a common variant near the CYP24A1 gene. CYP24A1 encodes the primary catabolic enzyme for active vitamin D and plays a critical role in calcium metabolism, highlighted by the discovery of inactivating mutations as a cause of hypercalcemia and nephrolithiasis. These data represent the first evidence that vitamin D catabolism is related to PTH regulation. The specific goals of this project are to extend these findings, by: 1) identifying rare variants associated with circulating PTH, 2) pinpointing functional variants associated with PTH concentrations, and 3) estimating the unconfounded causal association of serum PTH concentrations with hypertension, heart failure, and fracture using a Mendelian randomization approach.